Adverse Events After Receipt of TIV

Published for the 2010-11 Influenza Season; Adapted for the 2011-12 Influenza Season

Children

Studies support the safety of annual TIV in children and adolescents. The largest published postlicensure population–based study assessed TIV safety in 251,600 children aged younger than 18 years (including 8,476 vaccinations in children aged 6–23 months) who were enrolled in one of five health maintenance organizations within the Vaccine Safety Datalink (VSD) during 1993–1999. This study indicated no increase in clinically important medically attended events during the 2 weeks after inactivated influenza vaccination compared with control periods 3–4 weeks before and after vaccination. A retrospective cohort study using VSD medical records data from 45,356 children aged 6–23 months during 1991–2003 provided additional evidence supporting overall safety of TIV in this age group. During the 2 weeks after vaccination, TIV was not associated with statistically significant increases in any clinically important medically attended events other than gastritis/duodenitis, compared with 2–week control time periods before and after vaccination. Analysis also indicated that 13 diagnoses, including acute upper respiratory illness, otitis media, and asthma, were substantially less common during the 2 weeks after influenza vaccine. On chart review, most children with a diagnosis of gastritis/duodenitis had acute episodes of vomiting or diarrhea, which usually are self-limiting symptoms. The positive or negative associations between TIV and any of these diagnoses do not necessarily indicate a causal relationship. The study identified no increased risk for febrile seizure during the 3 days after vaccination. Similarly, no increased risk for febrile seizure was observed during the 14 days after TIV vaccination, after controlling for simultaneous receipt of measles-mumps-rubella (MMR) vaccine which has a known association with febrile seizures in the second week after MMR vaccination. Another analysis assessed risk for prespecified adverse events in the VSD, including seizures and Guillan-Barré Syndrome (GBS), after TIV during three influenza seasons (2005–06, 2006–07, and 2007–08). No elevated risk for adverse events was identified among 1,195,552 TIV doses administered to children aged younger than 18 years.

In a study of 791 healthy children aged 1–15 years, postvaccination fever was noted among 12% of those aged 1–5 years, 5% among those aged 6–10 years, and 5% among those aged 11–15 years. Fever, malaise, myalgia, and other systemic symptoms that can occur after vaccination with inactivated vaccine most often affect persons who have had no previous exposure to the influenza virus antigens in the vaccine (e.g., young children). These reactions begin 6–12 hours after vaccination and can persist for 1–2 days.

Data about potential adverse events among children after influenza vaccination are available from the Vaccine Adverse Event Reporting System (VAERS). Because of the limitations of passive reporting systems, determining causality for specific types of adverse events usually is not possible using VAERS data alone. Published reviews of VAERS reports submitted after administration of TIV to children aged 6–23 months indicated that the most frequently reported adverse events were fever, rash, injection-site reactions, and seizures; the majority of the limited number of reported seizures appeared to be febrile. Seizure and fever were the leading serious adverse events reported to VAERS in these studies; analysis of VSD data did not confirm an association with febrile seizures and influenza vaccination as observed in VAERS.

In April 2010, Australia's Therapeutic Goods Administration reported preliminary data indicating an elevated risk for febrile reactions, including febrile seizures, among young children in Australia who received the 2010 trivalent vaccine Fluvax Jr., the southern hemisphere inactivated trivalent vaccine for children manufactured by CSL Biotherapies. Refer to Update: Recommendations Regarding Use of CSL Seasonal Influenza Vaccine (Afluria) in the United States During 2010-11 and the 2011-2012 recommendations for updated information.

The risk for febrile seizures was estimated to be as high as five to nine cases per 1,000 vaccinated children aged younger than 5 years, and most seizures occurred among children aged younger than 3 years. Other influenza vaccines, including previous seasonal and pandemic influenza vaccines manufactured by CSL Biotherapies, have not been associated with an increased risk for febrile seizures among children in the United States or Australia. As of July 2010, no cause for the increased frequency of febrile reactions among young children who received the southern hemisphere CSL Biotherapies vaccine had been identified. ACIP will continue to monitor safety studies being conducted in Australia and might provide further guidance on use of Afluria, the northern hemisphere trivalent vaccine manufactured by CSL Biotherapies later in 2010. Immunization providers should consult updated information on use of the CSL vaccine from CDC and FDA.

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Adults

In placebo-controlled studies among adults, the most frequent side effect of vaccination was soreness at the vaccination site (affecting 10%–64% of patients) that lasted less than 2 days. These local reactions typically were mild and rarely interfered with the recipients' ability to conduct usual daily activities. Placebo-controlled trials demonstrated that among older persons and healthy young adults, administration of TIV is not associated with higher rates for systemic symptoms (e.g., fever, malaise, myalgia, and headache) when compared with placebo injections. One prospective cohort study indicated that the rate of adverse events was similar among hospitalized persons who either were aged 65 years and older or were aged 18–64 years and had one or more chronic medical conditions compared with outpatients. Among adults vaccinated in consecutive years, reaction frequencies declined in the second year of vaccination. In clinical trials, serious adverse events were reported to occur after vaccination with TIV at a rate of less than 1%. Adverse events in adults aged 18 years and older reported to VAERS during 1990–2005 were analyzed. The most common adverse events reported to VAERS in adults included injection-site reactions, pain, fever, myalgia, and headache. The VAERS review identified no new safety concerns. Fourteen percent of the TIV VAERS reports in adults were classified as serious adverse events, similar to proportions seen overall in VAERS. The most common serious adverse event reported after receipt of TIV in VAERS in adults was GBS. The potential association between TIV and GBS has been an area of ongoing research (see Guillain-Barré Syndrome and TIV). No elevated risk for prespecified events after TIV was identified among 4,773,956 adults in a VSD analysis.

Solicited injection-site reactions and systemic adverse events among persons aged 65 years and older were more frequent after vaccination with a vaccine containing 180 mcg of HA antigen (Fluzone High-Dose, sanofi pasteur) compared with a standard dose (45 mcg) (Fluzone, Sanofi pasteur vaccines) but were typically mild and transient. In the largest study, 915 (36%) of 2,572 persons who received Fluzone High-Dose reported injection-site pain, compared with 306 (24%) of the 1,260 subjects who received Fluzone. The pain was of mild intensity and resolved within 3 days in the majority of subjects. Among Fluzone High Dose recipients, 1.1% reported moderate to severe fever; this was substantially higher than the 0.3% of Fluzone recipients who reported this systemic adverse event. During the 6-month follow-up period, serious adverse events were reported in 6% of the High-Dose recipients and 7% of the Fluzone recipients.

Pregnant Women and Neonates

FDA has classified FluLaval, Fluarix (GlaxoSmithKline Biologicals), and Agriflu (Novartis Vaccines and Diagnostics Limited) influenza vaccines as "Pregnancy Category B" medications, indicating that animal reproduction studies have not demonstrated a fetal risk, but there are no controlled studies in pregnant women; all other influenza vaccines are classified as "Pregnancy Category C" medications, indicating that adequate animal reproduction studies have not been conducted. Available data do not indicate that any influenza vaccine causes fetal harm when administered to a pregnant woman, and any of the approved TIV formulations may be used for vaccinating pregnant women. One study of approximately 2,000 pregnant women who received TIV during pregnancy demonstrated no adverse fetal effects and no adverse effects during infancy or early childhood. A matched case-control study of 252 pregnant women who received TIV within the 6 months before delivery determined no adverse events after vaccination among pregnant women and no difference in pregnancy outcomes compared with 826 pregnant women who were not vaccinated. During 2000–2003, an estimated 2 million pregnant women were vaccinated, and only 20 adverse events among women who received TIV were reported to VAERS during this time, including nine injection-site reactions and eight systemic reactions (e.g., fever, headache, and myalgias). In addition, three miscarriages were reported, but these were not known to be related causally to vaccination. Similar results have been reported in certain smaller studies, and a recent international review of data on the safety of TIV concluded that no evidence exists to suggest harm to the fetus. The rate of adverse events associated with TIV was similar to the rate of adverse events among pregnant women who received pneumococcal polysaccharide vaccine in one small randomized controlled trial in Bangladesh, and no severe adverse events were reported in any study group.

Persons with Chronic Medical Conditions

In a randomized cross-over study of children and adults with asthma, no increase in asthma exacerbations was reported for either age group, and two additional studies also have indicated no increase in wheezing among vaccinated asthmatic children or adults. One study reported that 20%–28% of children aged 9 months–18 years with asthma had injection-site pain and swelling at the site of influenza vaccination, and another study reported that 23% of children aged 6 months–4 years with chronic heart or lung disease had injection-site reactions. A blinded, randomized, cross-over study of 1,952 adults and children with asthma demonstrated that only self-reported “body aches” were reported more frequently after receipt of TIV (25%) than placebo-injection (21%). However, a placebo-controlled trial of TIV indicated no difference in injection-site reactions among 53 children aged 6 months–6 years with high-risk medical conditions or among 305 healthy children aged 3–12 years.

Among children with high-risk medical conditions, one study of 52 children aged 6 months–3 years reported fever among 27% and irritability and insomnia among 25%, and a study among 33 children aged 6–18 months reported that one child had irritability and one had a fever and seizure after vaccination. No placebo comparison group was used in these studies.

Immunocompromised Persons

Data demonstrating safety of TIV for HIV-infected persons are limited, but no evidence exists that vaccination has a clinically important impact on HIV infection or immunocompetence. One study demonstrated a transient (i.e., 2–4 week) increase in HIV RNA (ribonucleic acid) levels in one HIV-infected person after influenza virus infection. Studies have demonstrated a transient increase in replication of HIV-1 in the plasma or peripheral blood mononuclear cells of HIV-infected persons after vaccine administration. However, more recent and better-designed studies have not documented a substantial increase in the replication of HIV. CD4+ T-lymphocyte cell counts or progression of HIV disease have not been reduced after influenza vaccination among HIV-infected persons compared with unvaccinated HIV-infected persons. Limited information is available about the effect of antiretroviral therapy on increases in HIV RNA levels after either natural influenza virus infection or influenza vaccination.

Data are similarly limited for persons with other immunocompromising conditions. In small studies, vaccination did not affect allograft function or cause rejection episodes in recipients of kidney transplants, heart transplants, or liver transplants.

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Hypersensitivity

Vaccine components rarely can cause allergic reactions, also called immediate hypersensitivity reactions, among certain recipients. Immediate hypersensitivity reactions are mediated by preformed immunoglobulin E (IgE) antibodies against a vaccine component and usually occur within minutes to hours of exposure. Symptoms of immediate hypersensitivity range from mild urticaria (hives) and angioedema to anaphylaxis. Anaphylaxis is a severe life-threatening reaction that involves multiple organ systems and can progress rapidly. Symptoms and signs of anaphylaxis can include but are not limited to generalized urticaria, wheezing, swelling of the mouth and throat, difficulty breathing, vomiting, hypotension, decreased level of consciousness, and shock. Minor symptoms such as red eyes or hoarse voice also might be present.

Allergic reactions might be caused by the vaccine antigen, residual animal protein, antimicrobial agents, preservatives, stabilizers, or other vaccine components. Manufacturers use a variety of compounds to inactivate influenza viruses and add antibiotics to prevent bacterial growth. Package inserts for specific vaccines of interest should be consulted for additional information. ACIP has recommended that all vaccine providers should be familiar with the office emergency plan and be certified in cardiopulmonary resuscitation. The Clinical Immunization Safety Assessment (95% CISA) network, a collaboration between CDC and six medical research centers with expertise in vaccination safety, has developed an algorithm to guide evaluation and revaccination decisions for persons with suspected immediate hypersensitivity after vaccination.

Immediate hypersensitivity reaction after receipt of TIV and LAIV are rare. A VSD study of children aged younger than 18 years in four health maintenance organizations during 1991–1997 estimated the overall risk for postvaccination anaphylaxis after childhood vaccine to be approximately 1.5 cases per 1 million doses administered, and in this study, no cases were identified in TIV recipients. Anaphylaxis occurring after receipt of TIV and LAIV in adults has been reported rarely to VAERS.

Information on considerations and recommendations regarding vaccination of persons reporting allergy to eggs is available in the 2011-2012 recommendations.

Hypersensitivity reactions to other vaccine components also can occur rarely. Although exposure to vaccines containing thimerosal can lead to delayed-type (Type IV) hypersensitivity, the majority of patients do not have reactions to thimerosal when it is administered as a component of vaccines, even when patch or intradermal tests for thimerosal indicate hypersensitivity. When reported, hypersensitivity to thimerosal typically has consisted of local delayed hypersensitivity reactions.

Ocular and Respiratory Symptoms After Receipt of TIV

Ocular or respiratory symptoms have been reported occasionally within 24 hours after TIV administration, but these symptoms typically are mild and resolve quickly without specific treatment. In some trials conducted in the United States, ocular or respiratory symptoms included red eyes (less than 1%–6%), cough (1%–7%), wheezing (1%), and chest tightness (1%–3%). However, most of these trials were not placebo-controlled, and causality cannot be determined. In addition, ocular and respiratory symptoms are features of a variety of respiratory illnesses and seasonal allergies that would be expected to occur coincidentally among vaccine recipients unrelated to vaccination. A placebo-controlled vaccine effectiveness study among young adults indicated that 2% of persons who received the 2006–07 formulation of Fluzone (sanofi pasteur) reported red eyes compared with none of the controls (p=0.03). A similar trial conducted during the 2005–06 influenza season indicated that 3% of Fluzone recipients reported red eyes compared with 1% of placebo recipients; however the difference was not statistically significant.

Oculorespiratory syndrome (ORS), an acute, self-limited reaction to TIV with prominent ocular and respiratory symptoms, was first described during the 2000–01 influenza season in Canada. The initial case-definition for ORS was the onset of one or more of the following within 2–24 hours after receiving TIV: bilateral red eyes and/or facial edema and/or respiratory symptoms (coughing, wheezing, chest tightness, difficulty breathing, sore throat, hoarseness or difficulty swallowing, cough, wheeze, chest tightness, difficulty breathing, sore throat, or facial swelling). ORS was first described in Canada and strongly associated with one vaccine preparation (Fluviral S/F, Shire Biologics, Quebec, Canada) not available in the United States during the 2000–01 influenza season. Subsequent investigations identified persons with ocular or respiratory symptoms meeting an ORS case-definition in safety monitoring systems and trials that had been conducted before 2000 in Canada, the United States, and several European countries.

The cause of ORS has not been established; however, studies suggest that the reaction is not IgE-mediated. After changes in the manufacturing process of the vaccine preparation associated with ORS during 2000–01, the incidence of ORS in Canada was reduced greatly. In one placebo-controlled study, only hoarseness, cough, and itchy or sore eyes (but not red eyes) were strongly associated with a reformulated Fluviral preparation. These findings indicated that ORS symptoms following use of the reformulated vaccine were mild, resolved within 24 hours, and might not typically be of sufficient concern to cause vaccine recipients to seek medical care.

Ocular and respiratory symptoms reported after TIV administration, including ORS, have some similarities with immediate hypersensitivity reactions. One study indicated that the risk for ORS recurrence with subsequent vaccination is low, and persons with ocular or respiratory symptoms (e.g., bilateral red eyes, cough, sore throat, or hoarseness) after receipt of TIV that did not involve the lower respiratory tract have been revaccinated without reports of serious adverse events after subsequent exposure to TIV.

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Revaccination in Persons Who Experienced Ocular or Respiratory Symptoms After Receipt of TIV

When assessing whether a patient who experienced ocular and respiratory symptoms should be revaccinated, providers should determine if concerning signs and symptoms of Ig-E mediated immediate hypersensitivity are present (see Immediate Hypersensitivity after Influenza Vaccines). Health-care providers who are unsure whether symptoms reported or observed after receipt of TIV represent an IgE-mediated hypersensitivity immune response should seek advice from an allergist/immunologist. Persons with symptoms of possible IgE-mediated hypersensitivity after receipt of TIV should not receive influenza vaccination unless hypersensitivity is ruled out or revaccination is administered under close medical supervision.

Ocular or respiratory symptoms observed after receipt of TIV often are coincidental and unrelated to TIV administration, as observed among placebo recipients in some randomized controlled studies. Determining whether ocular or respiratory symptoms are coincidental or related to possible ORS might not be possible. Persons who have had red eyes, mild upper facial swelling, or mild respiratory symptoms (e.g., sore throat, cough, or hoarseness) after receipt of TIV without other concerning signs or symptoms of hypersensitivity can receive TIV in subsequent seasons without further evaluation. Two studies indicated that persons who had symptoms of ORS after receipt of TIV were at a higher risk for ORS after subsequent TIV administration; however, these events usually were milder than the first episode.

Guillain-Barré Syndrome and TIV

The annual incidence of GBS is 10–20 cases per 1 million adults. Substantial evidence exists that multiple infectious illnesses, most notably Campylobacter jejuni gastrointestinal infections and upper respiratory tract infections, are associated with GBS. A recent study identified serologically confirmed influenza virus infection as a trigger of GBS, with time from onset of influenza illness to GBS of 3–30 days. The estimated frequency of influenza-related GBS was four to seven times higher than the frequency that has been estimated for influenza-vaccine–associated GBS.

The 1976 swine influenza vaccine was associated with an increased frequency of GBS, estimated at one additional case of GBS per 100,000 persons vaccinated. The risk for influenza-vaccine–associated GBS was higher among persons aged 25 years and older than among persons aged younger than 25 years. However, obtaining epidemiologic evidence for a small increase in risk for a rare condition with multiple causes is difficult, and no evidence consistently exists for a causal relation between subsequent vaccines prepared from other influenza viruses and GBS.

None of the studies conducted using influenza vaccines other than the 1976 swine influenza vaccine has demonstrated an increase in GBS associated with influenza vaccines on the order of magnitude seen in 1976–77. During three of four influenza seasons studied during 1977–1991, the overall relative risk estimates for GBS after influenza vaccination were not statistically significant in any of these studies. However, in a study of the 1992–93 and 1993–94 seasons, the overall relative risk for GBS was 1.7 (95% CI = 1.0–2.8; p=0.04) during the 6 weeks after vaccination, representing approximately one additional case of GBS per 1 million persons vaccinated; the combined number of GBS cases peaked 2 weeks after vaccination. Results of a study that examined health-care data from Ontario, Canada, during 1992–2004 demonstrated a small but statistically significant temporal association between receiving influenza vaccination and subsequent hospital admission for GBS. However, no increase in cases of GBS at the population level was reported after introduction of a mass public influenza vaccination program in Ontario beginning in 2000. Data from VAERS have documented decreased reporting of GBS occurring after vaccination across age groups over time, despite overall increased reporting of other non-GBS conditions occurring after administration of influenza vaccine. Published data from the United Kingdom's General Practice Research Database (GPRD) indicated that influenza vaccine was associated with a decreased risk for GBS, although whether this was associated with protection against influenza or confounding because of a “healthy vaccinee” effect (e.g., healthier persons might be more likely to be vaccinated and also be at lower risk for GBS) is unclear. A separate GPRD analysis identified no association between vaccination and GBS for a 9-year period; only three cases of GBS occurred within 6 weeks after administration of influenza vaccine. A third GPRD analysis indicated that GBS was associated with recent ILI, but not influenza vaccination.

The estimated risk for GBS (on the basis of the few studies that have demonstrated an association between vaccination and GBS) is low (i.e., approximately one additional case per 1 million persons vaccinated). The potential benefits of influenza vaccination in preventing serious illness, hospitalization, and death substantially outweigh these estimates of risk for vaccine-associated GBS. No evidence indicates that the case-fatality ratio for GBS differs among vaccinated persons and those not vaccinated. Preliminary data from the systems monitoring influenza A (H1N1) 2009 monovalent vaccines suggest that if a risk exists for GBS after receiving inactivated vaccines, it is not substantially higher than that reported in some seasons for TIV; analyses are ongoing to quantify any potential GBS risk.

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Use of TIV Among Patients with a History of GBS

The incidence of GBS among the general population is low, but persons with a history of GBS have a substantially greater likelihood of subsequently experiencing GBS than persons without such a history. Thus, the likelihood of coincidentally experiencing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons with no history of this syndrome. Whether influenza vaccination specifically might increase the risk for recurrence of GBS is unknown. Among 311 patients with GBS who responded to a survey, 11 (4%) reported some worsening of symptoms after influenza vaccination; however, some of these patients had received other vaccines at the same time, and recurring symptoms were generally mild. However, as a precaution, persons who are not at high risk for severe influenza complications and who are known to have experienced GBS within 6 weeks of receipt of an influenza vaccine generally should not be vaccinated. As an alternative, physicians might consider using influenza antiviral chemoprophylaxis for these persons. Although data are limited, the established benefits of influenza vaccination might outweigh the risks for many persons who have a history of GBS and who also are at high risk for severe complications from influenza.

Vaccine Preservative (Thimerosal) in Multidose Vials of TIV

Thimerosal, a mercury-containing antibacterial compound, has been used as a preservative in vaccines and other medications since the 1930s and is used in multidose vial preparations of TIV to reduce the likelihood of bacterial growth. No scientific evidence indicates that thimerosal in vaccines, including influenza vaccines, is a cause of adverse events other than occasional local hypersensitivity reactions in vaccine recipients. In addition, no scientific evidence indicates that thimerosal-containing vaccines are a cause of adverse events among children born to women who received vaccine during pregnancy. The weight of accumulating evidence does not suggest an increased risk for neurodevelopment disorders from exposure to thimerosal-containing vaccines. The U.S. Public Health Service and other organizations have recommended that efforts be made to eliminate or reduce the thimerosal content in vaccines as part of a strategy to reduce mercury exposures from all sources. Also, continuing public concerns about exposure to mercury in vaccines has been viewed as a potential barrier to achieving higher vaccine coverage levels and reducing the burden of vaccine-preventable diseases, including influenza. Since mid-2001, vaccines routinely recommended for infants aged younger than 6 months in the United States have been manufactured either without or with greatly reduced (trace) amounts of thimerosal. As a result, a substantial reduction in the total mercury exposure from vaccines for infants and children already has been achieved. ACIP and other federal agencies and professional medical organizations continue to support efforts to provide thimerosal-preservative–free vaccine options.

The U.S. vaccine supply for infants and pregnant women is in a period of transition as manufacturers expand the availability of thimerosal-reduced or thimerosal-free vaccine to reduce the cumulative exposure of infants to mercury. Other environmental sources of mercury exposure are more difficult or impossible to avoid or eliminate. The benefits of influenza vaccination for all recommended groups, including pregnant women and young children, outweigh concerns on the basis of a theoretic risk from thimerosal exposure through vaccination. The risks for severe illness from influenza virus infection are elevated among both young children and pregnant women, and vaccination has been demonstrated to reduce the risk for severe influenza illness and subsequent medical complications. In contrast, no harm from exposure to vaccine containing thimerosal preservative has been demonstrated. For these reasons, persons recommended to receive TIV may receive any age- and risk factor–appropriate vaccine preparation, depending on availability. An analysis of VAERS reports identified no difference in the safety profile of preservative-containing compared with preservative-free TIV vaccines in infants aged 6–23 months.

Nonetheless, some states have enacted legislation banning the administration of vaccines containing mercury; the provisions defining mercury content vary. LAIV and many of the single-dose vial or syringe preparations of TIV are thimerosal-free, and the number of influenza vaccine doses that do not contain thimerosal as a preservative is expected to increase (Table). However, these laws might present a barrier to vaccination unless influenza vaccines that do not contain thimerosal as a preservative are routinely available in those states.

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